Seminar :The Multiple Role of Antioxidant in The

Improvement of Life Quality

The role of OXIDATIVE STRESS
in CARDIOVASCULAR DISEASE
EPIDEMIOLOGY OF CAD
MORTALITY RATE ROSE BY 36 % IN
MEN AND 23 % IN WOMEN.
IN INDONESIA, MORTALITY RATE
ROSE BY 8,1 % (16,4 % IN 1992 TO
24,5 % IN 1995)
DATA FROM USA SUGGESTS THAT
REDUCTION IN CAD MORTALITY (14
%), MAY HAVE RESULTED FROM NEW
THROMBOLYTIC THERAPIES AND
LIPID- LOWERING DRUGS.
Atherosclerosis
Atherosclerosis is an inflammatory
disease of vascular wall initiated and
amplified by vascular oxidative stress
Atherosclerosis is low grade chronic
inflamatory disease
Am J Cardiology 2001;87(suppl):25c-32c
ATHEROSCLEROSIS COMPRISES
THREE ESSENTIAL COMPONENTS
1. ATHEROSIS THE ACCUMULATION OF
CHOLESTEROL- RICH GRUEL
ATHEROMA.
2. SCLEROSIS THE EXPANSION OF
FIBROUS TISSUE.
3. INFLAMMATION WHICH INVOLVES
MONOCYTES/ MAKROPHAGES, T -
LIMFOCYTES AND MAST CELLS
Newby (1997): Medicine international, 40,11:31-34
Risk Factors for Atherothrombosis
Risk Factors for Atherothrombosis
Atherosclerosis Atherosclerosis
Atherothrombotic Atherothrombotic Manifestations Manifestations
(MI, (MI, Ischemic Ischemic Stroke, Vascular Death) Stroke, Vascular Death)
Age Age
Obesity Obesity
Diabetes Diabetes
Hyperlipidemia Hyperlipidemia Hypercoagulable Hypercoagulable states states
Hypertension Hypertension
Genetics Genetics
Infection? Infection?
Homocysteinemia Homocysteinemia
Life-style (e.g., Life-style (e.g.,
smoking, diet, smoking, diet,
lack of exercise) lack of exercise)
Gender Gender
9
American Heart Association. Heart and Stroke Facts: 1997 Statistical Supplement; Wolf. Stroke 1990;21( American Heart Association. Heart and Stroke Facts: 1997 Statistical Supplement; Wolf. Stroke 1990;21(suppl suppl 2): 2):
II -4II -6; II -4II -6; Laurila Laurila et al. et al. Arterioscler Thromb Vasc Biol Arterioscler Thromb Vasc Biol 1997; 17: 2910-2913; 1997; 17: 2910-2913; Grau Grau et al. Stroke 1997;28:1724-1729; et al. Stroke 1997;28:1724-1729;
Graham et al. JAMA 1997;277: 1775-1781; Graham et al. JAMA 1997;277: 1775-1781; Brigden Brigden.. Postgrad Postgrad Med 1997;101(5):249-262. Med 1997;101(5):249-262.
Risk factors:
diabetes
hypertension
Vascular
dysfunction
Tissue injury
(MI, stroke)
Pathological
remodeling
Endothelial
Dysfunction
Target Organ
Damage
Mild
Severe

The Cardiovascular Continuum:
Targeting Mechanisms and Mediators

Adapted 2003 from Dzau V, Braunwald E. Am Heart J. 1991; Gibbons 1999.
Vascular disease
Target organ dysfunction
(HF, renal)
THE ROLES OF OXIDATIVE STRESS
(ROS)
(Pepine 1998)
Thrombosis Inflammation Vasoconstriction
Vascular lesion
and remodelling
Plaque rupture
| LDL | BP Diabetes Smoking
Oxidative stress
Endothelial dysfunction
+ NO - | Local mediators - | Tissue ACE-Alt
PAI-1
VCAM-1
ICAM-1
CYTOKINE
Growth
factors
matrix
Endothelial Proteolysis
Risk Factors
Clinical Sequelae
Proatherogenic mechanisms
Ross R. NEJM 1999;340:115-126
Vascular
inflammation
Progression and clinical complications of atherosclerosis
Risk Factors
Vascular ROS production
Endothelial dysfunction
(Reduced NO availability)
LDL
oxidation
Pro-inflammatory
gene expression(eg.
VCAM-1 and MCP-1,Il-6)
(Landmesser & Drexler,
2003)
The inflammatory cascade.
Pro-Inflamatory Risk
Factors
Primary Pro-Inflammatory Cytokines
(eg.IL-1,TNF-o)
ICAM-1
Selectin, HSPs,etc
Endothelium
and other cells
IL-6
Messenger Cytokine
CRP
SAA
Liver
Circulation
Libby, Ridker. Circulation 1999;100:1148-1150
Hypertension
Hyperglycemia/Diabetes
Hypercholesterolemia
Oscillatory Shear Stress

Il-6
Ang II
ICAM-1
VCAM-1

Mo

LDL
Endothelia
l
Cells

Mo

Lox
Nox
Nox

Foam
cells
Migration
Proliferation
Ox-LDL
MCP-1
O
2
0-

Smooth Muscle Cells
Fibroblasts
O
2
0-

Risk factor, oxidative stress, and early
atherosclerosis
Weiss D, Sorescu D, Taylor WR. Am J Cardiol 2001;87(suppl):25C-32C

Mo

Faktor Resiko : Merokok, Hipertensi, DM, dan lain-lain


|VCAM-1
|hs - CRP
| hs- IL-6
Monocyt Infiltration|
LDL
INFILTRATION |
Mo |
ROS
MM LDL|
ox - LDL |
Growth Factor
Proliferation and migration
of fibroblast and muscle cell
Foam Cell
Advanced Lesion
(Rupture and Hemorrhage)
Acute Myocardial Infarction
Fibrinogen|
TNFo
ENDOTHELIAL DYSFUNCTION
RISK FACTORS : HYPERTENSION, SMOKING, DM, HYPERLIPIDEMI
Hs CRP,
IL - 6
Oxidative Stress
HDL LDL Triglycerides
Oxidized LDL

Macrophage
Figure : Atherosclerotic Processes
(1) Oxidation of LDL depend on HDL/triglycerides
level; and (2) scavenging ox-LDL depend on
opsonizing by hs-CRP.
Pro- Atherogenic Effects of
0x- LDL
Chemotactic to Monocytes, smooth muscle
cells and T lymphocytes
Induced T cell activation and monocyte
differentiation
Inhibits macrophage motility, potentially
trapping macrophage
Cytototoxic to cells
Inhibits Endothelium Dependent
Relaxation Factor

(Brown 1996)
Pro- Atherogenic Effects of
0x- LDL
Induces the expression of adhesion
molecules on the endothelium
Induces Interleukin synthesis and
secretion by mcrophage
Increases tonus of vasomotor
Increases hypercoagulation

(Brown 1996)
Protective effects of
HDL
HDL is a reverse Cholesterol Transport
HDL decreased LDL oxidation
Decreased expression of VCAM-1 and MCP-1
Prevent the plaques stability and plaques
rupture
Prevent the endothelial cell integrity
Anti inflammation

(Miller 1986, Tjokroprawiro A, 2001)
EFFECTS OF DIABETES MELLITUS
ON CAD
(Giugliano 1996)
Hyperglycemia
Polyol
pathway
Protein
glycation

Oxidative
stress

O
2
-
/ NO
NO dependent
vasodilatation
Ca
2+

VSMC
proliferation
Heparan
sulphate
Glucose
autoxidation
Antioxidant
defence
Oxidative
factors
LDL
oxidation
Vasculopathy Ratinopathy Neuropathty Nephropathy
Hemorheologic
alterations
Coagulation
activation
Hypoxia
NCV

Endoneural
blood flow
Steady
Laminar
Blood Flow
Flow
Reversal
Effect of shear stress on endothelial cell ( Traub 1997
Antimigration
Antithrombotic
Promigration Prothrombotic
Pro-apoptosis
Pro-suvival
Low-mean shear
Shear Stress
Progrowth
Antigrowth
Ang II
PDGF
Endothelin I
Atherosclerotic Lesion
MCP-I
VCAM-I
NO
PGL
2
t-PA
Trombomodulin
Endothelium
Endothelium
Smooth muscle
Smooth muscle
NO
A primary effect of nicotine is to stimulate
the autonomic nervous system
Physiological and
PHYSIOLOGICAL & BIOCHEMICAL
CHANGES
| heart rate
| cardiac output
| blood pressure
| peripheral resistance

| fibrinogen levels


| platelet turnover

| platelet reactivity

| adipose tissue lipolysis
| plasma FFA
| myocardial oxygen consumption
HDL cholesterol
| LDL cholesterol

Clinical significance

CLINICAL SIGNIFICANCE


altered hemodynamics


fibrinogen is an independent risk factor
for stroke and coronary mortality

promotes thrombosis and atherosclerosis ?

alterations in coronary artery tone ?


ischemic injury ?


reduction in an independent negative risk
factor for CHD
increase in an independent positive risk
factor for CHD
|
|
.
|
|
.
Adelphi Communications ,1987
|
|
22
Endothelial dysfunction:
Pathogenesis of Atherosclerosis (I)
Monocyte
adhesion
Endothelial
adhesion
Monocyte
migration
Endothelial
permeability
Monocyte transmigration Vessel wall
Ross R, N Engl J Med 340 (1999) & Lusis AJ, Nature 407 (2000)
Monocy
te
Lipid-Cluster
0.5 m
Endothelial
barrier
Monocy
te
Subintima
10.078
x
Formation of an Advanced, Complicated lesion :
Falk et al, Circulation 92 (1995),Epstein, NEJM 14(1999)
Fibrous cap
formation
Macrophage
accumulation
Formation of
necrotic core
Pathogenesis of Atherosclerosis (III)
Vessel wall Coronary plaque with lipid core
STATINS STABILIZE VULNERABLE PLAQUE
Statin treated
ACE
ENDOTHELIAL CELL
ACE
SMOOTH MUSCLE CELL
INFLAMMATORY CELLS
Mast Cell (Chymase)
Macrophage (ACE)
Neutrophil
Tissue AII
VASOCONSTRICTION
INFLAMMATION
PLAQUE
INSTABILITY
THROMBOSIS
VASCULAR
REMODELING
Endothelin MCP-1
VCAM
Cytokines (IL-6)
Metalloproteinase
PAI-1
Platelet
aggregation
PDGF, FGF,
IGF, TGF-|
Proliferation
Migration
Extracellular
matrix modulation
ROLES OF MOLECULE IN ATHEROSCLEROSIS
(Dzau et al, 2001)
Angiotensin II-stimulated Release of
Interleukine 6 (IL-6) in Plaques
Role of cytokines in atherosclerosis:
adapt. from Schieffer et al., Hypertension 35 (2000)
1.0
0.5
1.5
10
-9
10
-8
10
-7
Stimulation of cultured smooth muscle
cells for 6 h
0
Angiotensin II (mM)
Control
I
n
t
e
r
l
e
u
k
i
n
e
-
6

P
r
o
t
e
i
n


(
n
g
/
m
l
)

Immunostaining of IL-6 (brown) in a human
coronary artery plaque
Foam-cell
Role of Macrophages and Angiotensin II:
Dysregulation of Extracellular Matrix
Synthesis in Vulnerable Plaques
fibrous
cap
Adapt. from Libby P, Circulation 91 (1995)
Matrix synthesis Matrix degradation
smooth
muscle cells
Collagen
Elastin
endothelial
cells
T-lymphocyte
Metallo-
proteinases
ACE
Peptides,
amino acids
TNF-o
M-CSF
MCP-1 etc.
INF-
TGF-
Ang II, IL-6
Plaque
INF- = Interferon-
Amino
acids
INF-




Nomenclature and main
histology
Sequences in progression
Main growth
mechanism
Earliest
onset
Clinical
correlation
Type I (initial) lesion isolated
macrophage foam cells
Type II (fatty streak) lesion
mainly intracellular lipid
accumulation
From
first
decade
Type III (intermediate) lesion
Type II changes & small
extracellular lipid pools
Clinically
silent
Type IV (atheroma) lesion
Type II changes & core of
extracellular lipid
Growth
mainly
by
lipid
accumu-
lation
From
third
decade
Type V (fibroatheroma)
lesion lipid core & fibrotic
layer, or multiple lipid cores &
fibrotic layers, or mainly
calcific, or mainly fibrotic
Accelerated
smooth
muscle
and
collagen
increase
Type VI (complicated) lesion
surface defect, hematoma-
hemorrhage, thrombus
Trombosis,
hematoma
From
fourth
decade
Clinically
silent
or
overt
III
II
I
IV
V
VI
PROGRESSION OF ATHEROSCLEROSIS ( Stary 2000)
Rupture of shoulder region with occlusive thrombosis:
from Burke et al., N Engl J Med 336 (1997)
x120 x30
ruptured cap
lipid core
human coronary artery, postmortem
Ruptured Plaque in Coronary Artery
Disease
Characteristics a Vulnerable
Plaques
Usually < 70 % stenosis
Eccentric shape with irregular borders
Large , lipid-rich core,high in cholesterol esters
Thin fibrous cap
High in macrophages
Low in smooth muscle cells and
collagen
Presence of inflammation
Tissue fatigue of the fibrous cap
( Doering , 1919 )
External triggering event :
Circadian variation
( morning )
Seasonal variation ( winter )
Physical exertion
Emotional stress
Internal triggering event :
+ Cap tension
+ Cap Compression
+ Cap flexion
+ Coagulability
+ Vasoconstriction
THROMBOSIS
Intermittent Occlusion
or Occlusion < 1 hour
Persistent
Occlusion
Unstablbe angina
Non-Q-Wave MI
Q-Wave MI
SCD
Role of triggering events in acute coronary events .
Vulnerable atherosclerotic plaque
( Doering , 1919 )
SCD = Sudden cardiac death
THE ROLES OF OXIDATIVE STRESS


EPIDEMIOLOGY
PATHOBIOLOGY
CLINICAL MANIFESTATION
TREATMENT
PROGNOSIS/EVALUATION
CONCLUSSION
Morbidity and mortality rate of atherosclerosis
were increased
Atherosclerosis is low grade chronic inflamatory
disease
Atherosclerosis is an inflammatory disease of
vascular wall initiated and amplified by vascular
oxidative stress
Hs CRP level and hs IL 6 level were
correlated with prognosis of atherosclerosis
Immunoregulatory treatments were the ideal
treatment of atherosclerosis

THANK YOU FOR
YOUR ATTENTION






Oxidative damage
potential
by free radicals
Defence capacity
by antioxidants
Internal Antioxidants
Enzymatics
- Superoxide Dismutase
- Glutathione Peroxydase
- Catalyse
Metal binding Proteins
- Albumin, Ferritins,
Ceruloplasmin
External Antioxidants
Non-Enzymatics
- Water-soluble : vitamin C, Thiols
- Lipid-soluble : vitamin E, b-caroten
Co-Q10 , flavonoids
Radicals
Superoxide
.
O2
-
Hydroxyl
.
OH
Peroxyl ROO
.
Alkoxyl RO
.
Hydroperoxyl HO2
.
Thiyl radical RS
.
Non-radicals
Hydrogen peroxide H2O2
Singlet oxygen
1
O2
Ozone O3
Peroxynitrite ONOO
-
Nitric oxide NO
.
Hypochlor acid HOCl
OXIDATIVE STRESS
Faisal Baraas : Buku REHABILITASI JANTUNG, 2003-2004
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